Recent biomedical technology advances have made it possible to detect breast cancer earlier, but options currently available to help patients with primary breast cancer or women at high risk of breast cancer are very limited. The long-term objective of our project is to identify and develop safe and efficacious agents, such as tocopherols, for prevention of breast cancer. Tocopherols are lipophilic phenolic antioxidants present in significant amounts in vegetable oils, such as soybean, corn, canola and cottonseed. Our laboratory has found that mixed tocopherols containing mainly gamma- and delta-tocopherols prevent an estrogen receptor (ER)- positive breast cancer. Based on our preliminary studies, we hypothesize that gamma- and delta-tocopherols, not alpha-tocopherol (known as a classic vitamin E), prevent breast cancer by inhibiting cell proliferation, inflammation, and oxidative stress, and by regulating receptor signaling pathways including peroxisome proliferator activated receptor (PPAR), ER and Her-2. The major specific aims of this project are to characterize the cancer preventive activities of mixed tocopherols as well as pure isoforms of tocopherols since it is not clear which tocopherol isomers are responsible for chemopreventive effects against breast cancer. Using two distinct preclinical models of breast cancer, we will determine the preventive efficacy of mixed tocopherols as well as the pure alpha-, gamma- and delta-tocopherols in an estrogen receptor (ER)-positive breast cancer and in an ER-negative/Her-2 positive breast cancer. Using immunohistochemistry, ELISA, Western Blot analysis and real time RT-PCR, we will investigate the efficacy and safety of tocopherols in animal models of breast cancer, analyze molecular markers and identify the mechanism of action of tocopherols in vivo. The proposed study will determine (a) the preventive efficacy of mixed tocopherols and the pure alpha-, gamma- and delta tocopherols individually in an ER-positive breast cancer model, (b) the preventive efficacy of mixed tocopherols and the pure alpha-, gamma- and delta tocopherols individually in a Her-2 positive breast cancer model using MMTV-Her-2/neu transgenic mice, and (c) the molecular mechanisms of the tocopherols in receptor signaling pathways such as PPAR, ER and Her-2. This project will provide a thorough understanding of cancer preventive activities of different tocopherols and their combinations, elucidate the detailed molecular mechanisms of cancer preventive actions on tocopherols, and provide fundamental information of tocopherols for future human breast cancer prevention studies.